Acalabrutinib plus venetoclax and rituximab in treatment-naive mantle cell lymphoma: 2-year safety and efficacy analysis.

This phase 1b study (NCT02717624) evaluated the safety and efficacy of acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive mantle cell lymphoma (TN MCL). Patients received acalabrutinib from cycle 1 until progressive disease or undue toxicity, rituximab for 6 cycles with maintenance every other cycle through cycle 24 or until progressive disease, and venetoclax, beginning at cycle 2, for 24 cycles. Twenty-one patients were enrolled, 95.2% completed induction (6 AVR cycles), and 47.6% continued maintenance with acalabrutinib. Thirteen (61.9%) patients had grade 3-4 adverse events (AEs), most commonly neutropenia (33.3%). Seven (33.3%) patients had COVID-19 infection (6 [28.6%] serious AEs; 5 [23.8%] deaths, all among unvaccinated patients). There were no grade ≥ 3 events of atrial fibrillation, ventricular tachyarrhythmias, major hemorrhages, or tumor lysis syndrome. Overall response rate (ORR) by Lugano criteria was 100% (95% confidence interval [CI]: 83.9, 100.0) with 71.4% complete response (CR). With median follow-up of 27.8 months, median progression-free survival (PFS) and overall survival (OS) were not reached. PFS rates at 1 and 2 years were 90.5% (95% CI: 67.0, 97.5) and 63.2% (34.7, 82.0), respectively; both were 95% after censoring COVID-19 deaths. OS rates at 1 and 2 years were 95.2% (95% CI: 70.7, 99.3) and 75.2% (50.3, 88.9), respectively; both were 100% after censoring COVID-19 deaths. Overall, 87.5% of patients with available minimal residual disease (MRD) data achieved MRD negativity (10-6; next-generation sequencing) during treatment. AVR represents a chemotherapy-free regimen for TN MCL and resulted in high ORR and high rates of MRD negativity.